Tremelimumab + Durvalumab(MEDI4736)+ Belinostat in Urothelial Carcinoma

Exclusion Criteria

• •Homozygous for UGT1A1\*28 allele or heterozygous or homozygous for UGT1A1\*60 orGilbert syndrome
• •Subject has received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy =\< 14 days or within 5 half-lives before starting study treatment, whichever is shorter
• •Prior treatment with durvalumab
• •Subject has received radiotherapy =\< 14 days before the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe
• •Subjects who have undergone major surgery =\< 3 weeks before starting study drug or who have not fully recovered from major surgery
• •Known additional malignancy that is active and/or progressive and requiring treatment.
• •Known brain metastases or cranial epidural disease
• •* Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment
• •Current evidence of uncontrolled, clinically significant intercurrent illness including, but not limited to, the following conditions:
• •* Cardiovascular disorders:
• •* Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias
• •* Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before the first dose
• •* Uncontrolled hypertension defined as a sustained systolic blood pressure \>= 160 mmHg or a diastolic blood pressure \>= 100 mmHg despite optimal management
• •* Note: Patients with uncontrolled hypertension who are not optimally managed may be rescreened once controlled hypertension is achieved
• •* Note: Patients with uncorrectable prolonged corrected QT (QTc) (Bezet formula) \> 480 msec or concomitant use of medications(s) with a known risk of inducing Torsade de Pointes if such treatment cannot be discontinued or switched to a different medication before starting the study drug
• •* Note: If a single electrocardiogram (ECG) shows a QTc with an absolute value \> 480 msec, two additional ECGs approximately 2 minutes apart must be performed within 30 minutes of the initial ECG, and the average of these three consecutive results for QTc will be used
• •* Adrenal insufficiency
• •* Interstitial lung disease (ILD)
• •Subjects with congenital long QT syndrome
• •Patients currently on or who will require valproic acid for any medical condition during the study
• •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[except for diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:
• •* Patients with vitiligo or alopecia
• •* Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• •* Any chronic skin condition that does not require systemic therapy
• •* Patients without active disease in the last 5 years may be included but only after consultation with the principal investigator
• •* Patients with celiac disease controlled by diet alone
• •Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
• •Patients who have received prior anti -PD-1, anti PD-L1 or anti CTLA-4:
• •* Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• •* All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
• •* Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• •* Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day.
• •Current or prior use of immunosuppressive medication within 14 days of cycle one day one, EXCEPT for the following permitted steroids:
• •* Intranasal, inhaled, topical steroids, eye drops or local steroid injection (e.g., intra-articular injection);
• •* Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent;
• •* Steroids as premedication for hypersensitivity reactions (e.g., computed tomography (CT) scan premedication)
• •History of active primary immunodeficiency
• •Known human immunodeficiency virus (HIV) infection with a detectable viral load at the time of screening
• •* Note: Patients on effective antiretroviral therapy with an undetectable viral load at the time of screening are eligible for this trial
• •Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis (TB) testing in line with local practice), hepatitis B (known positive hepatitis B virus \[HBV\] surface antigen (HBsAg) result), or hepatitis C
• •* Note: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• •Live attenuated vaccinations within 4 weeks of cycle one day one and while on trial is prohibited
• •Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute \[NCI\] CTCAE version \[v\]5.0 grade \>= 3)
• •Subjects taking prohibited medications. A washout period of prohibited medications for a period of at least 5 half-lives or as clinically indicated should occur before the start of treatment
• •Any other condition or disease that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures. (e.g. extensive peritoneal carcinomatosis).
• •Homozygous for UGT1A1\*28 allele or heterozygous or homozygous for UGT1A1\* 60 or Gilbert syndrome.